Clara Cell “10 kDa” protein (CC10) or uteroglobin (UG) is a small, homodimeric secretory protein produced by several mucosal epithelia and other organs of epithelial origin (Mukherjee, 1999). CC10 consists of two identical subunits of 70 amino acid residues, each with the “four helical bundle” secondary structure motif, joined in antiparallel orientation by two disulfide bonds between Cys 3 and 69′, 3′ and 69 (Matthews, 1994; Morize, 1997). The homodimer containing two disulfide bonds appears to be its primary, extracellular active form. In humans, the lung is the main site of CC10 production, while several other organs synthesize smaller amounts of mRNA encoding this protein (Singh, 1987; Sandmoller, 1994). CC10 is an anti-inflammatory and immunomodulatory protein that has been characterized with respect to various interactions with other proteins, receptors and cell types (reviewed in Mukherjee, 2007, Mukherjee, 1999, and Pilon, 2000). Lower levels of CC10 protein or mRNA have been found in various tissue and fluid samples for a number of clinical conditions characterized by some degree of inflammation including asthma (Lensmar, 2000; Shijubo, 1999; Van Vyve, 1995), pneumonia (Nomori, 1995), bronchiolitis obliterans (Nord, 2002), sarcoidosis (Shijubo, 2000), and in patients suffering from chronic rhinitis with recurrent sinusitis and nasal polyposis (Liu, 2004). Pulmonary epithelial cells, the body's primary source for endogenous CC10, are often adversely affected in these conditions, depleted or even ablated (Shijubo, 1999). Indeed, CC10 appears to be an autocrine and/or endocrine required for development of specific sets of non-ciliated respiratory epithelial cells and associated structures (Castro, 2000). Thus, it is still not known whether CC10 deficiency is a cause or an effect of the inflammation and/or the condition.
The obstruction of airflow in the nasal passages, as well as sinus pain and pressure, are known to be causes of significant morbidity in humans suffering from allergic rhinitis, non-allergic rhinitis, sinusitis, and nasal polyposis. Nasal rhinitis is an inflammation of the nasal passages and sinuses in the nasopharygeal cavity. There are two types of rhinitis, allergic and non-allergic. Non-allergic rhinitis is due to viral, bacterial, or other infection, to exposure to inhaled chemicals or other irritants, or may be idiopathic, while allergic rhinitis is due to exposure to inhaled allergens. Allergic rhinitis may be seasonal, such as allergy to tree or grass pollen; or it may be perennial, such as allergy to dust mites and common molds. Rhinitis ranges in severity from mild seasonal discomfort due to itching, sneezing, and nasal discharge for a few hours, days or weeks, to painful and debilitating chronic sinus inflammation that is often associated with recurrent bacterial infection. Chronic sinus inflammation in the presence of bacterial infection is sometimes referred to as chronic rhinosinusitis (“CRS”). CRS, leads to irreversible remodeling and scarring of airway epithelia and sinus tissue. These permanent changes to the nasal tissues result in a vicious cycle in which decreased ability to fight infection, both viral and bacterial, as well as a decreased ability to clear inhaled allergens and irritants, lead to even more exaggerated inflammatory responses, further exacerbating remodeling and fibrosis, and more severe or persistent infections. Theoretically, inflammation is reversible in the absence of infection, and should disappear as soon as the irritant, pathogen, or allergen is cleared from the local tissue. Therefore, the transition from seasonal or mild rhinitis to CRS can be attributed largely to chronic exposure to perennial allergens and/or recurrent bacterial infection of the inflamed nasal and sinus tissue, leaving the infection to persist even after the original rhinitis stimuli (allergen or irritant) is long gone. Indeed, patients with perennial allergies resulting in chronic rhinitis often experience recurrent bacterial infection (sinusitis) as the inflammatory response transitions from an allergen-stimulated response to an infection-stimulated response. These are the patients with severe persistent rhinosinusitis CRS disease and the highest morbidity. Chronic rhinitis, whether allergic or non-allergic, results in excess mucus production in, and swelling of, nasal passages that impairs breathing, disrupts sleep, and predisposes to repeated bacterial sinus infections. The sinus pain and pressure causes significant morbidity in this disease. Bacterial infection, whether acute or chronic, exacerbates these symptoms. In the most severe cases, nasal polyps grow in the nasal airways and slowly obstruct them. These polyps are non-malignant outgrowths of sinus tissue which can only be removed by sinus stripping surgeries. A patient with nasal polyps may undergo sinus stripping periodically since the polyps grow back after each removal.
However, determining whether rhCC10 can alleviate inflammation, and at what dosage, in patients suffering from nasal rhinitis, especially chronic rhinitis and rhinosinusitis, with or without nasal polyposis and in patients suffering from chronic or recurrent bacterial sinus infection has remained elusive. In fact, as shown below, recent work indicates that at dosages known and commonly used, rhCC10 is ineffective:
In a recent Phase II clinical study to evaluation the efficacy of intranasal rhCC10 to suppress nasal inflammation and rhinitis due to seasonal allergy, rhCC10 treatment resulted in a significant worsening of symptoms in one of six efficacy outcome measures compared to placebo (Widegren, et al., 2009). The remaining five efficacy outcome measures showed no difference between rhCC10 and placebo, although all trended in favor of placebo. RhCC10 was inferior to placebo in improving (increasing) peak nasal inspiratory flow and in mitigating rhinorrea caused by administration of aero-allergens. Table 1 shows comparative outcomes of patients while receiving rhCC10 versus outcomes in the same patients while receiving placebo, as measured during the last three days (days 5-7) of each treatment period.
TABLE 1P-values for statistical differences between rhCC10and placebo in five clinical outcome measures.Efficacy VariablerhCC10PlaceboP-valueMorning TNSS1.64 (0.21)1.50 (0.25).57Morning PNIF 136 (7) 136 (8).78Evening TNSS1.37 (0.28)1.54 (0.27).53Evening PNIF 145 (8) 147 (8).93TNSS-10 min5.67 (0.27)5.17 (0.32).09after challengePNIF-10 min after  93 (6) 102 (7).04*challenge*A p-value of <0.05 (less than 0.05) is considered to be a significant difference.P-values higher than 0.05 are not considered to be statistically significant.TNSS: Total nasal symptoms scorePNIF: Peak nasal inspiratory flow
This proof-of-concept study failed to demonstrate the overall efficacy of rhCC10 given once daily for seven days in this nasal allergen challenge model of seasonal allergic rhinitis. RhCC10, given 1.1 mg in 200 μL per day intranasally, did not favorably affect allergen-induced morning, post challenge or evening symptoms compared with placebo. A higher PNIF reflects greater airflow and a lower PNIF indicates restricted airflow. Morning as well as evening PNIF were unaffected by rhCC10, however, post challenge PNIF was modestly reduced by rhCC10 treatment compared to placebo, which did reach statistical significance. Symptom-scores and PNIF-levels reached in the placebo arm were very similar to those recorded historically in this model. Likewise, markers of inflammation in nasal lavage fluids, including levels of eosinophil cationic protein, myeloperoxidase, and alpha2-macroglobulin, and rhCC10 did not mediate any reduction in these markers compared to placebo. In this model, it has been demonstrated that corticosteroids inhibit morning, post-challenge as well as evening symptoms and these markers of inflammation in nasal lavages (Ahlstrom-Emanuelsson et al., 2002 & 2007) whereas anti-histamines reduce post-challenge symptoms only (Korsgren et al. 2007). Therefore, using this dose, dosing regimen, volume and spray method of intranasal administration, rhCC10 did not demonstrate anti-allergy, anti-inflammatory effects in all six clinical outcome measures or in all three inflammatory markers in nasal lavages.
Currently, most nasal rhinitis and rhinosinusitis are treated with various over-the-counter and prescription medications such as anti-histamines, decongestants, non-steroidal anti-inflammatory agents (“NSAIDS”) and various non-pharmacologic nasal sprays and irrigation solutions. Chromium nasal solutions, oral anti-histamines and leukotriene receptor antagonists treat symptoms but provide only a few hours of relief. Nasal oxymetazoline solutions are very effective at opening nasal passages but overuse results in a “rebound effect” and rapid loss of efficacy with worsening of symptoms. Side effects for these types of drugs include sore throat, dehydration of nasal tissues, and constipation, among others.
Furthermore, sinusitis is typically treated with oral antibiotics. Antibiotics range in side effects from mild to severe and can include constipation and other digestive problems, headache, dizziness, rashes, liver, kidney and bladder toxicity, muscle and joint pain, etc. Antibiotics can also cause hypersensitivity reactions, particularly in patients with recurrent sinusitis who have to take antibiotics repeatedly and eventually become allergic to them. Hypersensitivity reactions to antibiotics may occur without warning or previous signs of allergy and may be suddenly lethal.
For severe and/or chronic rhinosinusitis disease, physicians currently prescribe nasal corticosteroids, which reduce inflammation but often lose efficacy after a few weeks or months of continuous therapy. Oral corticosteroids are also efficacious but have many undesirable side effects when used for long periods of time. For example, in adults, cardiovascular complications, including hypertension and stroke, are major side effects of corticosteroid use. In children, corticosteroids impair normal growth and development. In all patients, corticosteroids lower the patient's immune function and leave them susceptible to infection of all types (bacterial, viral, fungal, etc.). Thus, safety is a major consideration in the choice of drugs and drug combinations used to treat, prevent or cure nasal rhinitis, especially chronic rhinosinusitis, nasal polyposis, chronic or recurrent bacterial sinus infection, their associated morbidities and other similar conditions.
There are several formulations, devices, and methods by which drugs may be administered intranasally to treat rhinitis, sinusitis, and rhinosinusitis. One method for administering local intranasal doses of drugs to the nasal passages and sinuses is the use of liquid drug formulations in spray bottle or spray pump devices that are converted to aerosols by being forced through a small aperture and sprayed into the anterior portion of the nasal cavity through each nostril.
Particle sizes generated by the aforementioned devices are in the 5-10 micron range, which maximizes delivery and local deposition of the drug in the nasal mucosa lining the nasopharygeal cavity. The nasal mucosa is comprised of a normally thin layer of mucus that overlays the wet epithelium in the nasal passages and sinuses of the nasopharyngeal cavity. Most 5-10 micron particles sprayed into the nostril will impact the non-ciliated epithelium in the anterior portion of the nasopharyngeal cavity. Once deposited at the site of impaction in the nasal mucosa, drugs may distribute throughout the mucosa and be cleared at various rates through the action of cilia and ciliated epithelial cells located in the posterior two thirds of the nasopharyngeal cavity that push towards the pharynx where the drug and mucus are swallowed. The local action of drugs deposited in the nasal cavity depends upon the particle size delivered, the formulation, and the rate of clearance. These factors affect the efficiency of local delivery and the length of time that the nasopharyngeal mucosa and epithelia are exposed to the drug before it is cleared.
The local action of intranasally administered drugs also depends upon the condition of the nasal mucosa and tissues at the time of delivery. For example, when the nasal passages are blocked by thick mucus, local delivery of drugs is very difficult, if not impossible.
Therefore, it is a significant challenge to find an agent, and a correct dosage for that agent, which alleviates airway obstruction, sinus pain and discomfort for a pro-longed period of time without serious side effects. There is therefore a need for new, more effective or longer-lasting agents and formulations thereof and administration and dosage regimens thereof, particularly in patients with chronic disease.